1. Field of the Invention
The present invention relates to a novel indene derivative, a preparation method for the same, and a pharmaceutical composition for preventing or treating retinal disease comprising the same as an active ingredient.
2. Description of the Related Art
The nerve tissue located in the center of the inner retina of the eye is called the macula. Most of the visual cells responding to the light stimulus are gathered here and the image of an object becomes focused in the center of the macula, suggesting that it plays a very important role in visual acuity. AMD (Age-related Macular Degeneration) is a chronic disease characterized by degeneration of macula pigment epithelium, Bruch's membrane, and choroidal capillaries of the macula. Anatomically, the neurosensory retina is located in front of the retinal pigment epithelium and depends on the retinal pigment epithelium for its nutrition, support, recirculation, and waste treatment. The said Bruch's membrane is a five-layered structure that is interposed between the choroid and the retinal pigment epithelium. The innermost layer is the basement membrane of the retinal pigment epithelium and the outermost layer is the basement membrane of the choroidal capillary endothelial cells. That is, AMD is a degenerative disease developed in the retinal pigment epithelium, Bruch's membrane and choroidal capillary complex.
This disease mainly occurs in people aged 50 years or older. In the West, this disease is the main cause of blindness in people over 60 and it is increasing in Korea. The cause of AMD is not clearly understood yet, but aging is the most possible risk factor (since the disease rate rapidly increases in those over 75). The most possible environmental cause is smoking. In addition, hypertension, obesity, genetic predisposition, excessive UV exposure, Low serum antioxidant concentration, etc, are regarded as the causes.
There are two types of macular degeneration, which are dry (nonexudative) macular degeneration and wet (exudative) macular degeneration. In the case of dry macular degeneration (dry AMD, nonexudative AMD, nonneovascular AMD), waste is deposited to form a yellow sediment called drusen under the retina and when this deposit is growing it disturbs blood flow to the retina particularly to the macula, resulting in the blurry vision and visual impairment. Dry macular degeneration does not cause sudden loss of vision, but it can progress to wet macular degeneration.
Wet macular degeneration (wet AMD, exudative AMD, neovascular AMD) is caused when angiogenesis is developed in the choroid below the retina. When the weak new blood vessel is broken, it results in bleeding or extrusion that causes degeneration of the macula area of the retina to cause vision impairment. Wet macular degeneration progresses rapidly, so that the visual acuity worsens within weeks and blindness may occur between two months and three years.
The treatment methods for macular degeneration known so far are photodynamic therapy (PDT) and anti-VEGF injection. In PDT, visudyne, the light-sensitive material is injected through blood vessel and when the light-sensitive material reaches to the newly formed blood vessels of the retina after a little while a special laser reacting to the light-sensitive material only is irradiated to the eyes to destroy the newly formed blood vessels selectively. However, there are many cases of recurrence even after this treatment, so it is often necessary to repeat the treatment. In the case of the repeated treatment, the retina itself may also be damaged.
The antibody (anti-VEGF) injection is an intravitreal injection of an antibody (anti-VEGF) that inhibits the formation and proliferation of new blood vessels by selectively binding to vascular endothelial growth factor (VEGF), which is an important factor for the generation and progression of new blood vessels. The protein antibodies used for the anti-VEGF injection are Lucentis and Avastin. Lucentis is a drug approved by FDA for the treatment of wet macular degeneration agent. Avastin is a drug approved for the treatment of cancer and is used for eye disease. However, the anti-VEGF injection is costly and is inconvenient because it cannot be dropped or applied to the eye and instead requires direct injection through the eye. It also needs a regular treatment once a month, suggesting that there is a risk of bleeding, pain, infection, retinal detachment, etc.
Therefore, studies to treat macular degeneration via different methods from the above have been going on. Recently, a strategy to develop a neuroprotectant that inhibits the death of the retinal nerve causing macular degeneration has been proposed (Retina today 2012. 64-65). Phosphorylation of RIPK1 (receptor-interacting serine/threonine-protein kinase 1) was observed in the retina of rats when the photoreceptor degeneration was induced by retinal detachment. It has been reported that the phosphorylation was reduced and the photoreceptor degeneration was also protected by the treatment of the RIPK1 enzyme activity inhibitor, Necrostain-1 (Nec-1) (Am J Pathol 2012. 181, 1634-1641).
In addition, there are other papers published continuously about the protection of retinal degeneration by the RIPK1 inhibitor Nec-1 (J Neurosci, 2013. 33(44), 17458-17468; Am J Pathol 2012. 181, 1634-1641; Oncotarget, 2011. 2(6), 497-509; Proc Natl Acad Sci USA, 2010. 107(50):21695-21700). This means that the RIPK1 enzyme activity inhibitor can be used as a macular degeneration treating agent.
Therefore, the present inventors confirmed that the novel indene derivative could inhibit RIPK1 enzyme activity when it was applied to the eye, suggesting that the novel indene derivative could be useful for the treatment of retinal disease such as macular degeneration, leading to the completion of the invention.